Deucravacitinib and orelabrutinib — two novel oral drugs under investigation for the treatment of systemic lupus erythematosus (SLE) — have performed well in early clinical trials reported as late-breaking abstracts at the annual European Congress of Rheumatology.
In the phase 2 PAISLEY study, up to 58% of patients treated with deucravacitinib versus 34% of placebo-treated patients met the primary study endpoint of an SLE Responder Index-4 (SRI-4) after 38 weeks of treatment. Deucravacitinib also “achieved or meaningfully improved” all of the secondary endpoints set out in the 363-patient trial and was reported to have a safety and tolerability profile that was generally similar to placebo.
“Deucravacitinib shows promise as a novel therapy for SLE and warrants further investigation in phase 3 trials,” said Eric F. Morand, MD, PhD, a clinical rheumatologist and head of the School of Clinical Sciences at Monash University in Melbourne.
In a separate, ongoing phase 1b/2a study designed to evaluate orelabrutinib as a potential treatment for SLE, no safety concerns were seen with the investigational drug, along with “trending efficacy,” that supports “further studies in larger and longer-term trials,” according to the study’s investigators.
“What sets these two new drugs apart from currently available targeted therapies are their mode of action,” said Md Yuzaiful Md Yusof, MBChB, PhD, who was not involved in either study.
“The results from the PAISLEY study are promising, and it’s good to see the patients recruited were of diverse ethnicity [50%–60% were White],” added Md Yusof, a senior research fellow within the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine and a consultant rheumatologist at Leeds Teaching Hospitals NHS Trust.
He noted that the placebo rate was also low: “This could be contributed to by keeping the background prednisolone dose low, which is often a challenge in designing SLE trials.”
Deucravacitinib — the Distant Cousin of the JAK Family?
“Deucravacitinib is a compound you might not have heard of before,” Morand said.
“It’s an inhibitor of a kinase called TYK2, which, broadly speaking, is a member of JAK [Janus kinase] family,” he explained in an interview. TYK2 regulates signal transduction downstream of receptors for interleukin (IL)-23 and IL-12 pathways and the type I interferon family.
“It’s a very finite set of cytokine signals” that are being blocked with deucravacitinib, he said, adding that this means it’s more directly targeting SLE pathogenic mechanisms than perhaps other JAK inhibitor compounds.
“It also means that it shouldn’t have some of the downsides of the other JAK inhibitors,” Morand said, “such as hematopoietic side effects, including cytopenias.”
The Phase 2 PAISLEY study
This study involved 363 patients with moderate to severe, active SLE were recruited and randomized to receive placebo (n = 90) or one of three doses of deucravacitinib: 3 mg twice daily (n = 91), 6 mg twice daily (n = 93), or 12 mg once daily (n = 89). Most patients were also taking multiple background therapies, but this was similar across the four treatment arms.
The SRI-4 primary endpoint after 38 weeks of treatment was met by 34.4% of patients who received placebo, but 58.2% of those treated with deucravacitinib 3 mg twice daily (P = .0006 versus placebo), 49.5% (P = .021) of those treated with 6 mg twice daily, and 44.9% (P = .078) treated with 12 mg once daily.
“All secondary outcome measures were achieved or meaningfully improved at week 48, including SRI-4, BICLA [British Isles Lupus Assessment Group-based Composite Lupus Assessment], low-level disease activity state [LLDAS], reduction in skin disease and reduction in arthritis,” Morand said.
In addition, early biomarker results showed reductions in double-stranded DNA titers and increases in serum C4 complement with deucravacitinib across the duration of the study.
In discussion, Morand was asked about the seemingly negative or inverse dose response seen in the trial, with the best results seen with the 3-mg twice daily dose, then lower effects seen with two higher doses.
“Our analysis is that it’s not an inverse dose response, but rather a flat dose response above the 3-mg [twice daily] dose,” he said, noting that there was a higher dropout rate because of adverse effects in the 12-mg once daily group and those participants were recorded as nonresponders.
“We think what we’ve seen here is that 3 mg twice daily is a sufficient dose and there was no additional therapeutic gain above that.”
Rates of adverse events (AEs), serious AEs, and AEs of interest were overall fairly similar between deucravacitinib and placebo groups. The most common side effects seen with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. Skin reactions, such as acne, rash, and pruritis, among others, were more common in deucravacitinib- than in placebo-treated patients.
Importantly, Morand noted that there were no major cardiac events or thrombotic events and no deaths seen in the study. There was no signal for an increase in serious or opportunistic infections, including herpes zoster. There was no effect on common laboratory parameters.
“We are honored to have played a role in this exciting work by helping to conduct this clinical trial through our Lupus Clinical Investigators Network of renowned North American academic centers.”
In an interview, he added: “We’re cautiously optimistic. Hopefully, if it continues to progress through phase 3, it’ll be the first oral agent that would be approved for lupus, notwithstanding prednisone and Plaquenil [hydroxychloroquine], back in the 50s.”
Orelabrutinib Phase 2 Study in SLE
Another approach to oral route of administration under investigation in SLE is the use of orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) that was approved in China in December 2020 for the treatment of certain lymphomas and leukemias.
The rationale for testing it in SLE comes from two preclinical studies that had suggested a possible benefit in reducing disease activity, explained Zhanguo Li, MD, PhD, professor at Peking University People’s Hospital in Beijing. He presented the results of an ongoing randomized, double-blind, placebo-controlled, phase Ib/IIa dose-finding study comparing three different doses of orelabrutinib (50, 80, and 100 mg, once daily) to placebo.
As in the deucravacitinib trial, the SRI-4 was used to assess the potential efficacy of orelabrutinib, although in a much smaller patient population (n = 92) and at a shorter time point (12 weeks). Results showed an 11%-20% difference between the percentage of patients who met SRI-4 response criteria with orelabrutinib and those on placebo, at a respective 46.5%, 53.3%, 56.3% and 35.7%.
SLE Disease Activity Index (SLEDAI) scores showed a similar benefit of orelabrutinib over placebo, with 54%-63% and 30% of patients, respectively, achieving a score of 8 or more.
Adverse event rates were similar to those of placebo with most events being of mild or moderate nature. Three patients treated with orelabrutinib experienced serious adverse events, of which one was grade 3, but there were no reported deaths.
Pharmacokinetic and pharmacodynamic data showed a dose effect, and nearly complete occupancy of BTK was achieved at all dose levels for 24 hours, consistent with once-daily dosing.
“BTK plays an important role in B-cell regulation, thus B-cell and myeloid-cell blockade through BTK inhibition is an interesting potential new target for SLE,” Md Yusof said.
“Data from this early dose-ranging trial is encouraging. No major safety signal apart from mild reduction in lymphocyte and white cell counts,” he added.
“There are still plenty of challenges ahead for this drug’s development, particularly as none of the BTK inhibitors have yet to succeed in phase 3 trials in rheumatic and musculoskeletal diseases,” Md Yusof said.
Early Days for Both Agents
While both seem currently promising, it’s very early days for deucravacitinib and orelabrutinib as possible new agents for SLE.
Aside from SLE, deucravacitinib is being tested across multiple immune-mediated diseases. This includes psoriasis, where two phase 3 trials – POETYK PSO-1 and POETYK PSO-2 – have already been completed, and psoriatic arthritis, where a phase 2 trial has been reported; all with positive results.
Phase 3 testing of deucravacitinib will go ahead and recruitment may start toward the end of this year, but it’ll take years to complete the studies, Morand said. Even if the trials prove positive, neither agent is going to be available for clinical use for several years.
A case in point is anifrolumab (Saphnelo), which Morand was involved in assessing. Despite gaining approval in the United States and across much of the world, the drug still going through reimbursement processes.
“The trial data, and lots of post hoc analysis, show clearly that it’s a major step forward in treating lupus,” he said in an interview, but “access is limited in most places, so hands-on experience with that new treatment is still limited for most clinicians.”
As for all the other new targeted approaches under investigation, “although there’s a lot of trial activity, there’s still a couple of years away before any of the current trials deliver new treatment. That’s if they provide positive findings. Indeed, there have been numerous agents that have shown promise at phase 2 but then fall at the final phase 3 hurdle, including baricitinib, which Morand reported on in a separate poster presentation.
Phase 3 data proved disappointing: “Results are not sufficiently positive for that to go forward,” he said, adding that “transitioning from a successful phase 2 to a successful phase 3 is challenging, and many products have failed.”
Morand added: “It’s a very exciting time to be in lupus research, and there’s a lot of optimism about the future. But when I go back to my clinic tomorrow, I treat my patients exactly the same as I did last week and last year.”
It’s yet to be seen if deucravacitinib will fulfill its early promise, but it’s off to an impressive start. A positive for patients is that it’s an oral drug, with the potential to improve access to treatment across the world where getting infusions may be an issue.
“These are some of the most exciting data that I’ve seen at the phase 2 level in terms of effect size across all the readouts that are used,” Morand said. “There’s no guesswork here; it worked across all the measures. That’s very reassuring.”
The PAISLEY study was sponsored by Bristol-Myers Squibb. Morand has acted as a consultant to the company and received research support for the conduct of the trial. He disclosed acting as a consultant or receiving research funding from AbbVie, Amgen, AstraZeneca, Biogen, Eli Lilly, EMD Serono, Janssen, Genentech, Servier, Novartis, and UCB.
Roy is the executive director of Lupus Therapeutics, which manages the Lupus Clinical Investigators Network based in North America. Lupus Therapeutics is the clinical trials arm of the Lupus Research Alliance, a nongovernmental, nonprofit funder of lupus research worldwide. The orelabrutinib study was sponsored by InnoCare Pharma. Li is the principal investigator for the trial but had no conflicts of interest to declare. Md Yusof disclosed receiving consultancy fees from Aurinia Pharmaceuticals.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.